The long-term goal ofthe research program. Genetic Models for Precision Cancer Medicine (Drs. Bult, Dai, and McKeon co-Leaders), is to develop novel therapeutic and diagnostic concepts for cancer by modeling and interrogating the complex genomics of human cancers. Research is organized around three inter-related themes, all of which involve the systems genomics ofthe cancer cell and its host environment. The first theme. Cancer Cell Robustness, aims to define the dynamic genome alterations at a systems level that generate primary drug resistance in a cancer and its subclones. The second theme. Genetic and Genomic Complexity, aims to measure and quantify genomic instability in primary cancers;to describe the associated genomic configurations;and to use defective maintenance systems for genome integrity for therapeutic advantage. The third theme. Progenitor Cell Biology, aims to define the genomic parameters of certain cancer progenitors;to reconstruct cancer states in primary cells using systems approaches;and to use this knowledge to provide effective combinatorial therapeutics. All program goals rely on interactions with program members who are developing advanced cross cutting technological approaches. The first approach, precision model development, includes efficient methods for humanizing cancer-relevant genomic regions in the mouse;tool strains for directing and visualizing temporal and tissue-specific gene expression;optimized immunodeficient mice for sustained engraftment of primary human cancers;and populations of mice that model human genomic heterogeneity. The second approach, genomic technologies, develops new high throughput DNA interrogation methodologies for detailed assessment of structural and sequence mutations and their transcriptional consequences. The third key technology is computational, including algorithms for modeling gene networks;ontology development that supports data integration and enables in silico modeling of gene functional associations;and informatics and database systems are essential for integrative studies and comparative genomic analyses. The 47 program members include 35 at Bar Harbor, 8 at Farmington, and 1 at Sacramento, together with 3 adjunct members from UC Davis Comprehensive Cancer Center, Eastern Maine Healthcare Systems, and Trinity University (TX). Through its emphasis on basic research and unique technology development, the program leverages funding from multiple NIH ICs in support of cancer focused research. In total the program is supported by $40,150,131 total costs in NCI and other peer reviewed cancer-related support in the last budget year. Over the past grant cycle, program members produced 1022 publications, including 10% intra-programmatic collaborations and 62% with collaborators external to JAX

Public Health Relevance

The JAXCC member retreat serves as the forum for planning that brings together all Cancer Center members from all campuses. Topics include collaborative projects;new resource and model development;technological and methodological innovations and their application to cancer research;and research areas for faculty recruiting, among others. Partial CCSG funding for the JAXCC member retreat is requested.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Center Core Grants (P30)
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Subcommittee G - Education (NCI)
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Jackson Laboratory
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Song, Delu; Grieco, Steve; Li, Yafeng et al. (2014) A murine RP1 missense mutation causes protein mislocalization and slowly progressive photoreceptor degeneration. Am J Pathol 184:2721-9
Chow, Kin-Hoe; Shin, Dong-Mi; Jenkins, Molly H et al. (2014) Epigenetic states of cells of origin and tumor evolution drive tumor-initiating cell phenotype and tumor heterogeneity. Cancer Res 74:4864-74
King Jr, Lloyd E; Silva, Kathleen A; Kennedy, Victoria E et al. (2014) Lack of response to laser comb in spontaneous and graft-induced alopecia areata in C3H/HeJ mice. J Invest Dermatol 134:264-6
Low, Benjamin E; Krebs, Mark P; Joung, J Keith et al. (2014) Correction of the Crb1rd8 allele and retinal phenotype in C57BL/6N mice via TALEN-mediated homology-directed repair. Invest Ophthalmol Vis Sci 55:387-95
Potter, Christopher S; Wang, Zhe; Silva, Kathleen A et al. (2014) Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling. PLoS One 9:e85666
Hosur, Vishnu; Johnson, Kenneth R; Burzenski, Lisa M et al. (2014) Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin. Proc Natl Acad Sci U S A 111:E2200-9
Roderick, Justine E; Tesell, Jessica; Shultz, Leonard D et al. (2014) c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood 123:1040-50
Korstanje, Ron; Caputo, Christina R; Doty, Rosalinda A et al. (2014) A mouse Col4a4 mutation causing Alport glomerulosclerosis with abnormal collagen ?3?4?5(IV) trimers. Kidney Int 85:1461-8
Grubb, Stephen C; Bult, Carol J; Bogue, Molly A (2014) Mouse phenome database. Nucleic Acids Res 42:D825-34
Inaki, Koichiro; Menghi, Francesca; Woo, Xing Yi et al. (2014) Systems consequences of amplicon formation in human breast cancer. Genome Res 24:1559-71

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